Benzopyrroloquinazolinones



United States Patent "Ce 3,423,412

Patented Jan. 21, 1969 3,423,412 (II), 2,3 dihydro 8 methoxybenzo[f]pyrrolo[1,2 a]- BENZOPYRROLOQUINAZOLINONES quinazolin-l 1(lH)-one (III), N-(l-cyano-6-methoxy-2- Edward C. Taylor, Princeton, N.J., and Youval Shvo, p y 'PY 'U-W Rehovoth, Israel (both of 1500 Spring Garden St., methoxy 2 naphthyDbutyramide (V), and 2 amino Philadelphia, Pa. 19101) 5 l-cyano-6-methoxynaphthalene (VI).

N0 Drawillg- Filed 1966, N 3 The following diagram illustrates schematically the CL .6 Claims preparation of the intermediate and product compounds Int. Cl. C07d 51/48 of the invention This invention relates to certain diazasteroid com- The star-ting material for their preparation is 6-methoxypounds and to intermediates for their preparation. In par- 10 2-naphthylamine [VII, J. Chem. Soc. 366 (1956)]. This ticular, the invention relates to a particular 12,14-diazacompound is carefully brominated in glacial acetic steroid having estrogenic activity and to various interacid, a d the Crude bfomihation Product acetylated With mediates therefor. acetic anhydride in pyridine. Recrystallization of the acet- 1|3r Br A NH2 A NI-ICOCH; NHCOCH3 a CHsO CHaO C aO VII VIII IX E m E m NH 01 -NH2 C1130 OHsO CHaO IV v CH3 CH CH3 T Q W NG T IQ CH O (EH 0 C aO III II I The invention is particularly concerned with the comylation product yields an ethanol-insoluble dibromo compound 1 acetyl 2,3 dihydro 8 methoxybenzo[f]pyrpound and an ethanol-soluble monobromo compound rolo[l,2-a]-quinazolin-l1(l2H)-one (I). (VIII). Reaction of the monombromo compound with cuprous cyanide in anhydrous pyridine gives the 1- cyano compound IX. Aqueous alkaline hydrolysis of IX gives the amino nitrile VI. Reaction of this compound with 4-chlorobutyryl chloride gives the butyramide V, which is cyclized to the pyrrolidinone IV with sodium methoxide in ethanol. Subsequent reaction of the pyrrolidinone with dry hydrogen chloride in anhydrous ethanol results in smooth cyclization to the diazasteroid III. When this compound is heated in a mixture of acetic anhydride and pyridine, the diacetyl derivative II is ob- Compound I may also be named, using steroid nomentained. Mild alkaline hydrolysis of II selectively cleaves datum, as 17 acetyl 3 InethOXY 13 T the N-acetyl group to give the final product I.

diazaestra 1,3,5(10),6,8,13(17) h ene 0 3 me- Compound I has estrogenic activity and has been demthOXY 18 I101 12,14 dialapfegha onstrated to give activity in rats at a dose of 20 mg./kg., The Present inventors believe that r when administered subcutaneously in a sesame oil formu- Compouhd I and intermediates II and III Tepfesent 316 lation. This compound is formulated for parenteral or first compounds heretofore prepared having the particular l use by combining it with standard pharmaceutical diazasteroid ring skeleton. excipients in a manner similar to that used in formulating Also part of the invention are certain intermediate comth estrogen-i0 agents pounds useful in preparing compound I. Among these Also part of the invention are the pharmaceutically accompounds are 1,12 diacetyl 2,3 dihydro 8 methox- 7O ceptable acid addition salts of compound I. These salts ybenzo[f]pyrrolo[l,2 a] quinazolin 11(12H) one include the hydrochloride, hydrobromide, sulfate, and

maleate, and are prepared in the conventional manner by combination of the basic compound and the acid, usually in the form of ethereal, alcoholic, or acetone solutions.

It will also be apparent to one skilled in the art of medicinal chemistry that certain obvious variants may be employed at particular stages of the synthetic sequence in order to obtain products with corresponding structures. These variants include use of a 6-ethoxy or 6-propoxynaphthylamine in place of 6-methoxy-2-naphthylamine in order to obtain diazasteroids with the appropriate 8-alkoxy group. Naphthylamines bearing substituents at other positions may also be used. Also, a substituted 4-chlorobutyramide may be used instead of the unsubstituted compound in order to obtain compounds having a correspondingly substituted S-membered pyrrole ring. Finally, acylation with lower acyl groups other than acetyl will result in the corresponding l-acyl product. Since all of the above variants are obvious to one skilled in the art, they are considered equivalent to the invention as specifically claimed.

The following examples illustrate the preparation of the compounds of the invention, but are not to be construed as limiting the scope of the invention.

EXAMPLE I 2-acetamido-1-bromo-6-methoxynaphthalene To a stirred, cooled solution of 23.5 g. (0.14 mole) of 2-amino-6-methoxynaphthalene in 100 ml. of glacial acetic acid was added slowly, and over a period of 30 min., a solution of 22 g. (0.14 mole) of bromide in 50 ml. of glacial acetic acid. Immediate precipitation occurred when the bromine was added. After addition was complete, the precipitated solid was collected by filtration, washed well with acetic acid followed by ether, and the crude product (46 g.) acetylated at room temperature with a mixture of 50 ml. of anhydrous pyridine and 100 ml. of acetic anhydride. After standing overnight at room temperature, the acetylation mixture deposited a crystalline solid which was collected by filtration and washed well with ethanol, followed by ether; yield 27 g., M.P. 165-173". This crude product, which was a mixture of monoand dibromo products, was separated by leaching with ethanol. The ethanol extracts upon concentration yielded 17.7 g. (47%) of 2-acetamido 1 bromo-6-methoxynaphthalene, M.P. 177-182. Recrystallization from ethanol raised the melting point to 183-186".

Analysis.--Calcd. for Ci H NO Br: C, 53.08; H, 4.11; N, 4.76. Found: C, 51.68; H, 4.01; N, 4.52.

EXAMPLE 2 Z-acetamido-1-cyano-6-methoxynaphthalene A mixture of 32 g. of Z-acetamido-1-bromo-6-methoxynaphthalene, 13 g. of cuprous cyanide (freshly prepared) and 20 ml. of anhydrous pyridine was heated in an oil bath at 200 for 3 hr. The hot black reaction mixture was poured with vigorous stirring into 2 1. of N aqueous ammonium hydroxide. The resulting suspension was stirred for 2.5 hr. and the brown solid filtered off, washed with dilute ammonium hydroxide and water and dried. Recrystallization of the crude product from aqueous ethanol gave Z-acetamido-1-cyano-6-methoxynaphthalene as colorless crystals, M.P. 198-200, in 57% yield.

EXAMPLE 3 2-amino-l-cyano-6-methoxynaphthalene A suspension of 10.0 g. of 2-acetamido-1-cyano-6methoxynaphthalene in 140 ml. of 1 N sodium hydroxide solution was heated under reflux with vigorous stirring for 30 min.; extensive foaming occurred. The resulting suspension was cooled, filtered, and the collected solid washed with dilute sodium hydroxide solution followed by water to give 7.8 g. (94%), M.P. 203-207"; the melting point was raised to 205207 by recrystallization from ethyl acetate.

4 Analysis.-Calcd. for C H N Oz C, 72.71; H, 5.09; N, 14.13. Found: C, 72.54; H, 5.02; N, 13.97.

EXAMPLE 4 4-chloro-N-(1-cyano-6-methoxy-2-naphthyl)butyramide To a suspension of 5.4 g. of 2-amino-l-cyano-6-methoxynaphthalene in 50 ml. of anhydrous pyridine was added slowly and with stirring 7.5 g. of freshly distilled 4-chlorobutyryl chloride. The reaction mixture was allowed to stand at room temperature overnight, poured over ice, and the solid which separated collected by filtration, washed with water, and recrystallized from ethanol; yield, 5.1 g. (61%), M.P. 158-165 Recrystallization from ethanol then gave while needles, M.P. 168-170".

Analysis.Calcd. for C H N O Cl: C, 63.3; H, 4.98; N, 9.25. Found: C, 63.3; H, 5.08; N, 9.14.

EXAMPLE 5 N-(1-cyano-6-methoxy-2-naphthyl)-2-pyrrolidinone To a suspension of 2.7 g. of 4-chloro-N-(l-cyan0-6- methoxy-Z-naphthyl)butyramide in ml. of anhydrous ethanol was added 3.6 g. of sodium methoxide. The mix ture became homogenous and turned pale yellow, and after a few minutes a colorless solid started to separate. The mixture was left overnight at room temperature, neutralized with acetic acid, diluted with ml. of water, and filtered. The collected solid was washed well with water and recrystallized from ethanol (charcoal) to give 1.8 g. (76%) of shiny plates, M.P. -167". Recrystallization from ethanol sharpened the melting point to 166- 167.

Analysis.-Calcd. for C H N O C, 72.16; H, 5.30; N, 10.52. Found: C, 72.10; H, 5.07; N, 10.56.

EXAMPLE 6 2,3-dihydro-8-methoxybenzol [f] pyrrolo l ,2-a quinazolin- 1 1 1H) -one Dry hydrogen chloride gas was passed for a period of 2.5 hrs. at room temperature through a suspension of 1.8 g. of N-(1-cyano-6-methoxy-2-naphthyl)-2-pyrrolidinone in 120 ml. of anhydrous ethanol. The reaction mixture was finally heated under refiux for 30 min., cooled, and the precipitated solid filtered off and washed well with ethanol; yield of the hydrochloride, 1.88 g. (92% This material was dissolved in 100 ml. of hot water and 1.8 g. of sodium acetate added; the crystalline colorless product which separated on cooling was filtered, washed with water, and recrystallized from a mixture of ethanol and dimethylformamide to give colorless crystals, M.P. 260- 270 dec.

Analysis.Calcd. for C H N O C, 72.16; H, 5.30; N, 10.52. Found: C, 71.96; H, 5.39; N, 10.28.

EXAMPLE 7 1, 1 2-diacetyl-2,3-dihydro-8-methoxy-benzo f] pyrrolo- [1,2-a]quinazolin-11(12H)-one A suspension of 2.1 g. of 2,3-dihydro-8-methoxybenzo- [f]pyrrolo[1,2-a]quinazo1in-11(1H)-one in 21 ml. of anhydrous pyridine and 21 m1. of acetic anhydride was heated under reflux for 1 hr., whereupon it became homogeneous. The reaction mixture was cooled to 0 and filtered, and the collected solid washed by water followed by ethanol and recrystallized from dimethylformamide to give 1.45 g. (60%) of pale yellow needles, M.P. 268- 270 dec.

Analysis.Calcd. for C H N 0 C, 68.56; H, 5.18; N, 8.00. Found: C, 68.77; H, 5.34; N, 8.22.

EXAMPLE 8 1-acetyl-2,3-dihydro-8-methoxybenzo [f] pyrrolo 1,2-a]- quinazolin-11(12H)-one A suspension of 4.52 g. of 1,12-diacetyl-2,3-dihydro-8 methoxybenzo[f]pyrrolo[1,2 alquinazolin l1(l2H)- one, 4.50 g. of sodium methoxide and 300 ml. of anhydrous ethanol was stirred under nitrogen at room temperature for 4.5 hrs. The reaction mixture was then neutralized with acetic acid, cooled and filtered to give 3.9 g. (98%). Recrystallization from dimethylformarnide gave yellow needles, M.P. 272-275".

Analysis.Calcd. for C H N O C, 70.11; H, 5.23; N, 9.09. Found: C, 70.32; H, 5.25; N, 9.26.

We claim:

1. A compound of the formula OTNK J. p C1110 where R is hydrogen or acetyl.

2. A compound as claimed in claim 1, where R is hydrogen, being the compound 1-acetyl-2,3-dihydro-8-methoxybenzo [f] pynrolo l ,2-a] quinazolin-l 1 12H) -one.

3. A compound as claimed in claim 1, where R is acetyl, being the compound l,12-diacetyl-2,3-dihydro-8-methoxybenzo [f] pyrrolo 1,2-a] quinazolin-l 1 12H)-one.

4. 2,3 dihydro 8 methoxybenzo [f]pyrrolo[1,2 a]- quinazolin-11(1H)-one.

5. A pharameutically acceptable acid addition salt of the com-pound of claim 2.

6. A saft as claimed in claim 9, where the salt is the hydrochloride.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner.

R. V. RUSH, Assistant Examiner.

U.S. Cl. X.R. 

1. A COMPOUND OF THE FORMULA 